approach to patients with suspected muscle disease - muscle diseases final - 2.pdf · approach to...

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Approach to patients with Approach to patients with suspected muscle diseasesuspected muscle diseaseApproach to patients with Approach to patients with suspected muscle diseasesuspected muscle disease

Bakri Elsheikh, MBBSAssistant Professor

Department of NeurologyDepartment of NeurologyOhio State University Medical Center

ObjectivesObjectives

P id i f li i l h• Provide an overview of clinical approach to muscle disease based on patterns of weakness

• Discuss the role of different diagnostic tests in muscle disease

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P id i f li i l h• Provide an overview of clinical approach to muscle disease based on patterns of weakness

• Discuss the role of different diagnostic tests in muscle disease

Goals of evaluation Goals of evaluation • What is the site of the lesion?

– Is it muscle?– Where in the muscle?

• What is the cause of the myopathy ?– Hereditary: MD; Myotonias; Metabolic; Mitochondrial– Acquired:Acquired: Inflammatory; Endocrine; Toxic; Systemic

illness• What is the treatment ?

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Shot gun approach Shot gun approach

• Time constrains “Reality of the practice of medicine”!

• Focused & systematic approach is the most efficient approach

• “ Good history and examination ..can not be yreplaced”

• Search for clues in the H &P

Chief complaint Chief complaint • Negative sx.

― Weakness• Positive sx.

M l iWeakness

― Fatigue

― Atrophy

― Exercise intolerance

― Myalgia

― Cramp

― Contracture

― Myotonia to e a ce

― Periodic paralysis

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History of present illnessHistory of present illness• Age at symptom onset

– Birth vs. childhood vs. adulthood

– Mild childhood sx. are usually missed

• Evolution of symptoms – Acute/sub-acute vs. Chronic vs. Static

• Weakness

– Proximal vs. Distal vs. Cranial

• Fatigue & exercise intolerance– Metabolic and mitochondrial myopathies

– Cardiopulmonary; depression; systemic illness

• Myoglobinuria

More History More History

• PMH

– Thyroid, parathyroid, adrenal, GH, cancer, HIVThyroid, parathyroid, adrenal, GH, cancer, HIV

– Cardiac, pulmonary, musculoskeletal

• FH

– X-linked, AD, AR, maternal transmission

• SH

Smoking >>paraneoplastic– Smoking >>paraneoplastic

• Meds

– Statins, amiodarone, chloroquine, Colchicine, prednisone

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Examination Examination • Pattern of weakness (6 major patterns)

– Symmetry

– Location (proximal/distal)

– Cranial (ocular, facial, pharyngeal)

• Calf hypertrophy

– True vs. pseudo

• Other features

Frontal balding cataract face muscle– Frontal balding, cataract, face muscle wasting

– Dysmorphic features

– Rash

– Liver enlargement

“ Limb-Girdle” Proximal Weakness Pattern

“ Limb-Girdle” Proximal Weakness Pattern

• Most common

• Symmetric

• Proximal; Proximal >> Distal• Proximal; Proximal >> Distal

• Neck muscle involvement

• Remember to examine muscles against gravity

• Examples

– Acquired: PM, DM, endocrine and toxic myopathies

– Hereditary: DMD, BMD, LGMD, Pompe disease

• Mimickers

– SMA, LEMS, CIDP

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Vignette 1Vignette 1

• 45 y/o WF

– WeaknessWeakness

– Difficulty going up steps

– Facial and knuckles rash

– Swelling around the eyes

– Difficulty swallowingDifficulty swallowing

– Recent h/o ovarian cancer

– CK normal

DermatomyositisDermatomyositis

• Idiopathic inflammatory myopathy (IIM)– PM, IBM, NM

• Adults and children

• F > M

• Onset: Wks- Months

• Weakness: Symmetric; Proximal & Distal

• Myalgia y g

• Facial weakness

• Dysphagia ~30%

• Rash

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DermatomyositisDermatomyositis rash rash DermatomyositisDermatomyositis rash rash

Diffuse erythematous

rash on face & scalpErythematous macular rash neck & anterior chest (V-sign)

Heliotrope rash refer to purplish (brown) eyelids discoloration

often with periorbitaledema Gottron’s sign scaly

lesions over knuckles and elbows Erythematous rash – post. Upper

back & shoulder (shawl sign)

Calcification Calcification • Calcifications in

subcutaneous tissues

• Pressure points (buttocks, knees, and elbows)

• Tend to occur in inadequately treated patients IMACSp

• More in children (30-70%)

• Difficult to treat

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Muscle EnzymesMuscle Enzymes• Amato et al. Ann Neurol 96

― DM (9 pts) 758 (± 6929)― PM (22 pts) 5097 (±

7706)

Wong et al. Am J Clin Path. 83

• 1537 subjects

• High CK group (52 520 U/L))

― sIBM (15 pts) 698 (± 430)

• CK in normal in 10% Dermatomyositis pts

• Should be elevated in all PM and NM pts

CK l l d ’t l t ith

• High CK group (52-520 U/L)– Black men

• Intermediate CK group (25-345 U/L)– Black women – Non-black men

• CK level doesn’t correlate with weakness

• AST,ALT, LDH elevation– GGT to follow liver

disease

• Low CK group (25-145 U/L)– Non-black women

Normal CK in slowly progressive myopathies

• 12 pts• Muscle discomfort 92%• P & D weakness 50%• Joint pain 75%• Pulmonary involvement 50%• Negative Jo-1 in five tested• EMG: Normal 36%; irritable

myopathy 18%; non-irritable 45%

• Bx.– Perimysial pathology (92%)– Acid phosphatase positive

cellularity (83%)

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EMGEMG

Fibs & PSW Myopathic MUPs

Muscle MRIMuscle MRI• Abnormal signal

– Edema

– Inflammation

– Fatty replacement

• Chronic disease

• Muscle atrophy

• Current use

– Identify biopsy side

– Known myositis & normal CK

• Flare vs. steroid Mammen A. Ann. N. Y. Acad. Sci. 2009

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Other Laboratory work upOther Laboratory work up

• ANA positive

– DM 24-60%• ESR normal

• Auto-antibodies

• Jo-1 20% IIM

• Anti SRP Myocarditis and NM• Anti-SRP Myocarditis and NM

• Mi-2 15-20% DM

DM-Muscle BiopsyDM-Muscle Biopsy• Multifocal • Severity vary within muscle

specimen• Characteristic feature is

perifascicular atrophy– Seen in 50%-75%

• Perivascular inflammation – Macrophages– B-cells

CD4+ >>PDCS– CD4+ >>PDCS• Gene microarray studies

– Increase expression of type 1 interferon &

proteins they regulate Amato AA, Russel JA 2008

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MalignancyMalignancy

• Increased incidence of malignancy • Usually after age 40• Highest near time of diagnosis (1-3year)• Still some risk after 3 year• Presence of malignancy doesn’t correlate with

disease severity• Types of associated cancer

Breast o ar l ng pancreas non Hodgkin’s– Breast, ovary, lung, pancreas, non-Hodgkin’s, stomach, colorectal, melanoma

– Nasopharyngeal (Asia) • Treatment of malignancy may improve myositis

Evaluation Evaluation

• Suspected inflammatory myopathy

• √ ck √ TSH

• Muscle Biopsy• Baseline Dexa scan• Malignancy screen• √ ck √ TSH

• √ Autoimmune screen• √ Jo-1 √ CBC √INR• EMG

– √ myopathy √ mm irritability √ exclude mimickers ex.

• Malignancy screen (> 40)– Examination

• General /skin– Ct chest

• Lung fibrosis– Ct abdomen/pelvis

myotonia– Multiple proximal and

distal muscles – Thoracic paraspinal

p– Mammogram– Colonoscopy– Prostate

• Swallow evaluation

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Treatment SummaryTreatment Summary

• RCT are rare

• Corticosteroids is considered 1st line Rx

• IVIG is a costly Rx of DM

• There is a role for steroid and IVIG sparing agents– Methotrexate, cyclosporine, mycophenolate mofetil

• Patients should be encouraged to participate in research trials

Distal weakness Pattern Distal weakness Pattern • Make sure neuropathy (sensory) & MND

(asymmetry) are excluded ( y y)

• Examples

– Myotonic dystrophy

– Distal myopathies

– Myofibrillar myopathy

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VignetteVignette• 42 y/o female

• Stiffness of the hands• x 5 years• x 5 years

• Swallowing difficulty

• Cataract surgeryage 20

• Pacemaker

• Excess daytime sleepiness

Myotonic Dystrophy 1 (DM1)Myotonic Dystrophy 1 (DM1)

• Most common adult muscular dystrophy• AD inheritance

Si l l i h 19 13 3• Single locus in chromosome 19q13.3 • dystrophia myotonica protein kinase (DMPK)• 3' untranslated region with increase in

trinucleotide CTG repeats• Multisystem disease

– Cardiac conduction defects …..PacemakerCardiac conduction defects …..Pacemaker– Cardiomyopathy– Hypersomnia– Cognitive Impairment– Gastrointestinal symptoms – Insulin insensitivity

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Myotonic Dystrophy 2 (DM2)

Myotonic Dystrophy 2 (DM2)

• Share many DM1 features – >>> hip flexor weakness>>> hip flexor weakness

– <<< facial weakness

• AD inheritance

• Single locus at chromosome 3q 21.3

• Zinc finger protein 9 gene (ZNF9)

• CCTG repeat expansion in intron 1• CCTG repeat expansion in intron 1

• Disease severity independent of number of repeats

• Screening for cardiac and pulmonary abnormalities similar to DM1

Molecular genetic studies Molecular genetic studies

http://www.ncbi.nlm.nih.gov/sites/GeneTests/

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VignetteVignette

• 23 y/o man– Difficulty running

and toe walking since age 3

– No arm weakness or sensory symptoms

– FH: Pos. with male to male transmission

– Weak ankle dorsiflexor and big toe extensor

– CK normal

– EMG myopathic

Distal myopathiesDistal myopathiesDisease Gene Age at

onsetInitial muscles CK Muscle Bx

Welander 2p 13 > 40 Finger and wrist extensors

1-4 X Rimmed vacuoles

Udd TTN >35 Anterior leg compartment

1-4X ± Rimmed vacuoles

Markesbery-Griggs

ZASP >40 Anterior leg compartment

1-3X Vacuolar & myofibrillar

Distal myotlinopathy

MYOT > 40 Posterior > anterior leg


Laing (MPD1) MYH 7 < 20 Anterior leg & neck flexors

1-3X Type 1 fiber atrophy

Vocal cord & pharyngeal (MPD2)

MATR3 35-60 Asymmetric lower leg and hand; dysphonia


( )

New Finnish (MPD3)

8 p22-q11 12 q13-22

>30 Hands or anterior leg 1-4 X Dystrophic; rimmed vacuoles

Nonaka GNE 15-20 Anterior leg compartment

< 10 times Rimmed vacuoles

Miyoshi DYSF 15-30 Posterior leg compartment

> 10 times Myopathic

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Distal myopathiesDistal myopathiesDisease Gene Age at

onsetInitial muscles CK Muscle Bx

Welander 2p 13 > 40 Finger and wrist extensors


Udd TTN >35 Anterior leg compartment

1-4X ± Rimmed vacuoles

Markesbery-Griggs

ZASP >40 Anterior leg compartment


Distal myotlinopathy

MYOT > 40 Posterior > anterior leg


Laing (MPD1) MYH 7 < 20 Anterior leg & neck flexors

1-3X Type 1 fiber atrophy

Vocal cord & pharyngeal (MPD2)

MATR3 35-60 Asymmetric lower leg and hand; dysphonia


( )

New Finnish (MPD3)

8 p22-q11 12 q13-22

>30 Hands or anterior leg 1-4 X Dystrophic; rimmed vacuoles

Nonaka GNE 15-20 Anterior leg compartment

< 10 times Rimmed vacuoles

Miyoshi DYSF 15-30 Posterior leg compartment

> 10 times Myopathic

Proximal Arm Distal Leg Weakness Pattern (Scapuloperoneal)

Proximal Arm Distal Leg Weakness Pattern (Scapuloperoneal)

• Scapular winging • Scapular stabilizer weakness• Ankle stabilizer weakness• Asymmetry• Examples

FSHD– FSHD– LGMD– Acid maltase deficiency – Myofibrillar myopathy– Scapuloperoneal dystrophy

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Vignette Vignette

• 32 y/o female

• Facial weaknessFacial weakness

• Sleep eyes open

• Can’t whistle

• Difficulty raising arm above shoulder

• Shoulder painShoulder pain

• Pos. FH

FacioscapulohumeralFacioscapulohumeral dystrophydystrophyFacioscapulohumeralFacioscapulohumeral dystrophydystrophy

• 3rd most common MD

• Autosomal dominant linked to 4q35

• Deletion of 3.3 kb repeated sequence (D4Z4)

• Symptoms begin < age 20 in ~ 80%

• Typically begins in face; subtle or absent~4%

• Shoulder weakness, pain presenting c/o in 80%

• ~20% asymptomatic at dx

• CK mildly elevated

• 15% will require use of wheel chair

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Distal arm/Proximal Leg Weakness Pattern

Distal arm/Proximal Leg Weakness Pattern

• Distal forearm (wrist and finger flexor) and quad (Knee extensor) weakness

• Asymmetric

• Facial weakness -mild

• Example

– Inclusion body myositis

Sporadic Inclusion Body MyositisSporadic Inclusion Body Myositis• Commonest IIM after age 50

• Refractory PM

• = IBM or dystrophy

• More common in men

Forearm atrophy/ weakness

• More common in men

• Onset: Months-Years

• Dysphagia ~30-60%

• CK Mild to moderate

• Not responsive to immunosuppressive Rx

Quads weakness

Facial weakness 1/3

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Ptosis With or Without Ophthalmoplegia Pattern

Ptosis With or Without Ophthalmoplegia Pattern

• Ptosis alone

– Myotonic dystrophy

– Cong. Myopathy

– Myofibrillar Myopathies

• Ptosis and Opthalmoplegia

– OPMD

– Mitochondrial myopathy Ex. CPEO

– NMJ disorders Ex. MG

Vignette Vignette • 35 y/o

• Droopy eyelids

• Progressive ophthalmoplegia

• Proximal weakness

• Short stature

• Third degree AV block

Kearns-Sayre Syndrome

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Neck Extensor WeaknessNeck Extensor Weakness• Dropped head

syndrome

• DD: ALS, MG, Parkinson’s

• Examples

– INEM

– Inflammatory myopathymyopathy

– FSHD

– MD

– Congenital Myopathy

Isolated Neck Extensor MyopathyIsolated Neck Extensor Myopathy

• 7th decade or older

• Weakness over days to WksWks.

• Dull or burning neck pain

• Some report deltoid weakness

• EMG changes limited to cervical (mid to lower) ce ca ( d to o e )and upper thoracic spine

• MRI fatty replacement and atrophy of the paraspinal muscles.

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Take Home Message Take Home Message • Detailed history and exam are fundamental steps

to reaching a specific diagnosis • Muscle disease can be distinguished from other

disorders causing weakness• Pattern of weakness help guide the work up• Normal CK does not exclude muscle disease• EMG and muscle biopsy are valuable diagnostic

tools • Molecular genetic testing is emerging as a useful

noninvasive diagnostic tool ~ not for fishing g gexpedition

• Symptomatic management and screening for complications decrease morbidity and mortality in muscle disease pts

• Multidisciplinary team approach for MD pts is crucial

The Patient with The Patient with MyalgiaMyalgia: : Myths, Muscle Diseases, and Myths, Muscle Diseases, and

(A Little) Madness(A Little) Madness

The Patient with The Patient with MyalgiaMyalgia: : Myths, Muscle Diseases, and Myths, Muscle Diseases, and

(A Little) Madness(A Little) Madness(A Little) Madness(A Little) Madness(A Little) Madness(A Little) Madness

Miriam Freimer, MDDepartment of Neurology

Vice Chair for Clinical AffairsVice Chair for Clinical AffairsAssociate Professor of Clinical Neurology

Ohio State University

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Muscle Pain EpidemiologyEpidemiology

Muscle Pain EpidemiologyEpidemiology

•• Most common complaint in NM clinicsMost common complaint in NM clinicsMost common complaint in NM clinicsMost common complaint in NM clinics–– ~50% of referrals for muscle biopsy~50% of referrals for muscle biopsy

•• Prevalence of diffuse myalgia ~10%Prevalence of diffuse myalgia ~10%–– ~20% prevalence of focal myalgia~20% prevalence of focal myalgia

•• 2020--50% complain of muscle tiredness50% complain of muscle tiredness00 50% co p a o usc e t ed ess50% co p a o usc e t ed ess–– Up to 25% of primary care OP visitsUp to 25% of primary care OP visits

•• 90% of myalgia patients have fatigue90% of myalgia patients have fatigue–– 95% of CFS patients have myalgia95% of CFS patients have myalgia

Muscle Pain Problems for ClinicianProblems for Clinician

Muscle Pain Problems for ClinicianProblems for Clinician

•• PainPain onlyonly symptom in many patientssymptom in many patientsPain Pain onlyonly symptom in many patientssymptom in many patients

–– No signs of disease (No signs of disease (egeg weakness) weakness)

–– Difficult to assess at bedsideDifficult to assess at bedside

•• Myalgia may arise from many sourcesMyalgia may arise from many sources

–– Ortho rheum gen med psychOrtho rheum gen med psych–– Ortho, rheum, gen med, psychOrtho, rheum, gen med, psych

–– May not be related to muscle diseaseMay not be related to muscle disease

•• Many patients are “Many patients are “undiagnosableundiagnosable” in the ” in the usual senseusual sense

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Diagnoses in Myalgia Patients

Mills and Edwards, 1983Mills and Edwards, 1983

Diagnoses in Myalgia Patients

Mills and Edwards, 1983Mills and Edwards, 1983

DiagnosisDiagnosis # Pts.# Pts. %%Enzyme defects 16 15%Inflammatory myopathy 8 7%Neurogenic disorders 7 6%Endocrine & metabolic 6 6%Endocrine & metabolic 6 6%No diagnosis 72 66%

Total 109 100%

Filosto et al, Neurology 2007Filosto et al, Neurology 2007

•• Many myalgia patients DO have biopsy Many myalgia patients DO have biopsy abnormalities, but they are usually nonabnormalities, but they are usually non--specificspecific–– They They usually do NOT lead to a diagnosisusually do NOT lead to a diagnosis

•• Routine biopsy NOT indicated in patients with Routine biopsy NOT indicated in patients with isolated myalgia; careful patient selection is isolated myalgia; careful patient selection is neededneeded

•• Important info for referring doctors AND patients!Important info for referring doctors AND patients!

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Approach to Patient with Myalgia


Approach to Patient with Myalgia


•• Basic approach myalgia patient Basic approach myalgia patient

–– When to biopsy and when to not!When to biopsy and when to not!

•• Present overview of myalgia in generalPresent overview of myalgia in general

–– Terminology & classificationTerminology & classification

–– Highlight mistakes & myths seen in clinicHighlight mistakes & myths seen in clinic–– Highlight mistakes & myths seen in clinicHighlight mistakes & myths seen in clinic

•• Discuss 4 muscle diseases with isolated Discuss 4 muscle diseases with isolated generalized myalgia (i.e. no weakness)generalized myalgia (i.e. no weakness)

–– Including the “FIncluding the “F------ word” (fibromyalgia)word” (fibromyalgia)

Patient with MyalgiaCase Case PresentationPresentation

Patient with MyalgiaCase Case PresentationPresentation

68 yo male, 6 mos hx

• Severe myalgias, AM stiffness, ADL loss – “Walking in glue”

• “ I don’t feel good!”

• Lost 10 pounds

• CK, EMG normal

• Referred for muscle bx. for presumed PM

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Evaluation of Muscle PainEvaluation of Muscle Pain

Screening examinationLabs. CBC, ESR, TFTs, lytes)

Tender Tender

Normal

<5x nl

CK elevated

FET

Weak, abn EMG, CK

Neuro. eval - strength, endurance testingSerum CK , electrodiagnostic studies

FM

Tender points

present?

PMR, MADStatins

Tender points

absent?

Repeat

<5x nl No other

abn

Biopsy

>5x normal,other sx

FET, Genetictesting

Biopsy

The Patient with Muscle PainGeneral Approach General Approach

The Patient with Muscle PainGeneral Approach General Approach

•• Careful history attending to type of painCareful history attending to type of pain

–– Consideration of localization/pathogenesisConsideration of localization/pathogenesis

–– Analysis of disease possibilitiesAnalysis of disease possibilities

•• Exam. with attention to strength testing!Exam. with attention to strength testing!

–– Most common source of error!!Most common source of error!!

•• Judicious lab testsJudicious lab tests•• Judicious lab tests Judicious lab tests

–– Routine (e.g. CKRoutine (e.g. CK and EMG)and EMG)

–– Specialized (FET, biopsy, genetic testing) Specialized (FET, biopsy, genetic testing)

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Muscle Pain Terminology

Types of Pain

Muscle Pain Terminology

Types of Pain

•• “I don’t have any pain at all…it just hurts!”“I don’t have any pain at all…it just hurts!”

•• “Pain” can mean numbness, stiffness, “Pain” can mean numbness, stiffness, tingling, restlessness, burning, swellingtingling, restlessness, burning, swelling

•• Useful to classify 4 types of muscle painUseful to classify 4 types of muscle pain

–– Contractures Contractures ---- Cramps Cramps

–– StiffnessStiffness ---- Aching myalgiaAching myalgia

Deep Aching -Localized

Muscle Differential DiagnosisMuscle Differential Diagnosis

Deep Aching -Localized

Muscle Differential DiagnosisMuscle Differential Diagnosis

PostPost--exercise myalgia (“weekend warrior”)exercise myalgia (“weekend warrior”)Infiltrating processes (e.g. tumor, Infiltrating processes (e.g. tumor, sarcoidsarcoid))Focal pressure necrosisFocal pressure necrosisTraumaTraumaLocalized infections (bacterial, parasitic)Localized infections (bacterial, parasitic)Localized infections (bacterial, parasitic)Localized infections (bacterial, parasitic)Venous occlusionVenous occlusionArterial ischemia (thrombotic or embolic)Arterial ischemia (thrombotic or embolic)Referred “muscle” painReferred “muscle” pain

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Examples of Focal MyalgiaExamples of Focal Myalgia

Sarcoid Myopathy Diabetic Thigh Infarct

Diffuse Muscle PainInflammatory Muscle Disease*

Diffuse Muscle PainInflammatory Muscle Disease*

*Only ~25% of PM/DM pts. have significant *Only ~25% of PM/DM pts. have significant myalgiasmyalgias

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Deep Aching - GeneralizedDifferential Diagnosis

Deep Aching - GeneralizedDifferential Diagnosis

With weaknessWith weakness

•• PM DM (20PM DM (20 25%)25%)Without weaknessWithout weakness

I f tiI f ti•• PM, DM (20PM, DM (20--25%)25%)

•• HypothyroidismHypothyroidism

•• Mitochondrial dx.Mitochondrial dx.

•• MyotonicMyotonic dystrophy dystrophy 22

•• InfectiousInfectious

•• Infectious Infectious myalgia (esp. myalgia (esp. viral)viral)

•• Toxic myopathies Toxic myopathies ((egeg lovastatin)lovastatin)

MADDMADD•• Infectious Infectious myopathiesmyopathies

•• Other rare Other rare myopathiesmyopathies

•• MADD MADD

•• PMRPMR

•• FibromyalgiaFibromyalgia



Tender Tender

Normal

<5x nl

CK elevated

FET

Weak, abn EMG, CK


FM

Tender pointspresent?

PMR, MADStatins

Tender pointsabsent?

Repeat

<5x nl No other

abn

Biopsy

>5x normal,other sx

FET, Genetictesting

Biopsy

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Statin MyopathyTerminology & EpidemiologyStatin MyopathyTerminology & Epidemiology

ACC & AHA & NHLBI list 4 entities (2002)• Statin myopathy – ANY muscle complainty p y p

– Up to 15-25% (including isolated CK rise ?)

• Statin myalgia – pain without CK rise– 2-9% overall (up to 20% in some series)

• Statin myositis – pain/weakness/CK rise– Rare with biopsy proven inflammation, < 0.2% cases

• Statin rhabdomyolysis – CK > 10x normalStatin rhabdomyolysis CK > 10x normal– < 1 per million scripts for all but cerivastatin (Baycol)

SO• Since 105 million patients should be on statins

– 5-6 million new statin myopathy cases!! ? Underestimate!

Statin MyopathyPredisposing FactorsPredisposing FactorsStatin MyopathyPredisposing FactorsPredisposing Factors

Patient Factors• Increased age

Female sex

Medication Factors• High statin dose• Agent (eg lovastatin)• Female sex

• Small stature• Liver, kidney

dysfunction• Hypothyroidism• Post-operative

Di t ( f it

Agent (eg lovastatin)• Polypharmacy

– Colchicine– Erythromycin– Cyclosporine– Niacin– Calcium channel

• Diet (eg grapefruit juice)

• Genetic predisposition• Underlying myopathy

blockers– Nefaxodone– Anti-fungals – Fibric acids

(gemfibrozil)Cause still unknown!

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Statin Myopathy CharacteristicsFranc et al, 2003Franc et al, 2003

Statin Myopathy CharacteristicsFranc et al, 2003Franc et al, 2003

•Symptoms can occur at any time in course!•Symptoms do NOT always resolve with drug DC

Statin MyopathyManagement

Statin MyopathyManagement

•• Tricky, since the meds ARE helpfulTricky, since the meds ARE helpful–– Cannot just blindly stop in all patientsCannot just blindly stop in all patients

•• RechallengeRechallenge with other drug with other drug may may be optionbe option–– Usually doesn’t work!Usually doesn’t work!

•• Symptomatic treatment (gabapentin, PT, Symptomatic treatment (gabapentin, PT, NSAIDs, NSAIDs, shortshort course steroids)course steroids)

•• Little evidence for aerobic exercise, CoQ10, Little evidence for aerobic exercise, CoQ10, carnitinecarnitine

•• “Tincture of time” sometimes best option“Tincture of time” sometimes best option–– Some patients have persistent symptoms!Some patients have persistent symptoms!

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Grable-Esposito et alMuscle & Nerve 2010

Grable-Esposito et alMuscle & Nerve 2010

• 25 pts. on chronic statins (only 4 with pain)

–– WeaknessWeakness, high CK after statins DCd

– Necrotizing myopathy on muscle bx.

– Responded to immunosppressive drugs

– 24 required multiple agents

– 15 relapsed on withdrawal of agents

Statin Myopathy ManagementStatin Myopathy ManagementSymptoms Symptoms (myalgia, CK, weakness(myalgia, CK, weakness)

SxSx ResolveResolve Sx. PersistSx. PersistDC StatinDC Statin

SxSx. Resolve. Resolve Sx. PersistSx. Persist

ObserveObserve

Manage with diet,Manage with diet, Treat symptomsTreat symptoms

ProgressionProgressionStableStable

WeaknessWeaknessniacin, bile resinsniacin, bile resins

Muscle bx.Muscle bx.

Higher CKHigher CK

ResolveResolve PersistPersist

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Patient with MyalgiaCase Presentation

Patient with MyalgiaCase Presentation

68 yo male, 6 mos hx

• Severe myalgias, AM tiff ADLAM stiffness, ADL loss – “Walking in

glue”

• “ I don’t feel good!”

L t 10 d• Lost 10 pounds

• CK, EMG normal

• Referred for muscle bx. for presumed PM

The Patient with MyalgiaCase PresentationCase Presentation

The Patient with MyalgiaCase PresentationCase Presentation

• Examination NORMAL including strengthExamination NORMAL, including strength

• Screening blood work normal

– Including CK, aldolase

• EMG - completely normal (but painful)

• Muscle biopsy deferred

• ESR = 80 mm/hour; diagnosis of PMR

• Prednisone 40 mgs/day

– Complete resolution in 2 days

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Polymyalgia RheumaticaEpidemiologyEpidemiology

Polymyalgia RheumaticaEpidemiologyEpidemiology

•• Technically not muscle disease per seTechnically not muscle disease per se

•• One of most common causes of myalgiaOne of most common causes of myalgia

–– 600600--1000/100,000 in patients >age 501000/100,000 in patients >age 50

–– Incidence of ~50/100,000 per yearIncidence of ~50/100,000 per year

•• Mean age of onset 70 (90% > age 60)Mean age of onset 70 (90% > age 60)

•• Female predominance of 3:1Female predominance of 3:1

•• 50% of giant cell arteritis (GCA) get PMR50% of giant cell arteritis (GCA) get PMR

–– 1515--20% of PMR develop GCA20% of PMR develop GCA

Polymyalgia RheumaticaSymptoms

Polymyalgia RheumaticaSymptoms

•• Myalgia, stiffness, aching,Myalgia, stiffness, aching,Neck shoulders hipsNeck shoulders hips–– Neck, shoulders, hipsNeck, shoulders, hips

•• Worse in AM, movementWorse in AM, movement

–– Stiffness, “gelling”Stiffness, “gelling”

•• Systemic symptoms in 40%Systemic symptoms in 40%

–– Fevers, depression, wt. Fevers, depression, wt. loss, poor sleep, loss, poor sleep, , p p,, p p,anorexia, anemia, anorexia, anemia, arthritisarthritis

–– Similar to FMSimilar to FM

•• Tenderness rare (Tenderness rare (ddxddx FM)FM)

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Polymyalgia RheumaticaLaboratory

Polymyalgia RheumaticaLaboratory

•• CK and EMGs normalCK and EMGs normal

•• ESR very high (>100)ESR very high (>100)

–– 1515--20% 20% -- normalnormal ESRESR

•• Temporal artery bx. Temporal artery bx. only only in patients with GCA in patients with GCA sxssxs. . ((notnot in isolated PMR)in isolated PMR)

•• Muscle bx. not indicatedMuscle bx. not indicated

–– NonNon--specific changesspecific changes

–– Pathogenesis ?Pathogenesis ?•• Synovial painSynovial pain

Polymyalgia RheumaticaTreatment

Polymyalgia RheumaticaTreatment

•• Prednisone (10Prednisone (10--40 mg/day) causes 40 mg/day) causes immediate immediate and and dramaticdramatic improvementimprovement

–– Diagnostic as well as therapeuticDiagnostic as well as therapeutic

•• GCA requires higher dosesGCA requires higher doses

–– 6060--100 mg orally or 1.0 100 mg orally or 1.0 gmgm IVIV

•• Treat symptoms and ESRTreat symptoms and ESRTreat symptoms and ESRTreat symptoms and ESR

–– Taper slowly when Taper slowly when sxssxs. under control. under control

–– Usually requires 1Usually requires 1--2 2 yearsyears treatmenttreatment

•• 10% require treatment for over 10 years!10% require treatment for over 10 years!

35

Fibromyalgia – The MadnessEpidemiology

Fibromyalgia – The MadnessEpidemiology

•• >3000 Medline articles >3000 Medline articles since 1990!since 1990!

•• ~2% population in US~2% population in US

–– (3.4% F; 0.5% M)(3.4% F; 0.5% M)

–– 33--6 mil. people in U.S.6 mil. people in U.S.

•• 7575--90% cases in women90% cases in women

•• Any age (children); Any age (children); especially elderly (7% of especially elderly (7% of women > age 60)women > age 60)

•• 20% of rheum. 20% of rheum. ppatients; atients;

–– 3rd most common 3rd most common (after OA, RA)(after OA, RA)

FibromyalgiaNotable QuotesNotable Quotes

FibromyalgiaNotable QuotesNotable Quotes

•• “I don’t know what that term means.”“I don’t know what that term means.”

•• “It’s just a waste“It’s just a waste--basket term.”basket term.”

•• “That’s just a grab“That’s just a grab--bag diagnosis.”bag diagnosis.”

•• “Doctor’s diagnose that when they really “Doctor’s diagnose that when they really don’t know what’s wrong with someone.”don’t know what’s wrong with someone.”

•• “I don’t think it’s a ‘real’ disease at all ”“I don’t think it’s a ‘real’ disease at all ”•• I don t think it s a real disease at all.I don t think it s a real disease at all.

•• “All these people are just depressed.”“All these people are just depressed.”

•• “They’re all trying to get disability.”“They’re all trying to get disability.”

36

FibromyalgiaClinical FeaturesClinical Features

FibromyalgiaClinical FeaturesClinical Features

•• Diffuse myalgia, stiffness, aching, joint painDiffuse myalgia, stiffness, aching, joint pain

•• Proximal predominance; can be anywhereProximal predominance; can be anywhere

•• Insidious onset (? postInsidious onset (? post--infectious, trauma)infectious, trauma)

•• Fatigue, morning stiffness, nonFatigue, morning stiffness, non--restorative restorative sleep in 75%sleep in 75%sleep in 75%sleep in 75%–– AnxietyAnxiety ----SwellingSwelling ----HeadachesHeadaches

–– IBSIBS ----ImbalanceImbalance ----DysuriaDysuria

–– Raynaud’sRaynaud’s ----DysmenorrheaDysmenorrhea ----DysesthesiasDysesthesias

New ACR Diagnostic CriteriaArthArth Care Res 2010;62:600Care Res 2010;62:600--1010

New ACR Diagnostic CriteriaArthArth Care Res 2010;62:600Care Res 2010;62:600--1010

• Widespread pain > 3 mos.; no other cause

( )• Widespread pain index (WPI) > 7 and symptom severity (SS) scale score > 5 OR

– WPI 3-6 and SS score > 9

• NO tender point exam! 88% correlation

37

FM - Pathogenic Hypotheses

Summary

FM - Pathogenic Hypotheses

Summary

•• FM is NOT a muscle dx. (40 neg. studies)FM is NOT a muscle dx. (40 neg. studies)

•• FM is NOT entirely psych (30FM is NOT entirely psych (30--50% with dx.)50% with dx.)

•• FM is NOT a single disease (multiple studies)FM is NOT a single disease (multiple studies)

•• May be central up regulation of pain pathways May be central up regulation of pain pathways (decreased subs. P in CSF) (decreased subs. P in CSF)

–– Sorensen (1995) Sorensen (1995) -- improved with IV ketamine improved with IV ketamine (NMDA ant.) in blinded, cont. trial of 31 pts.(NMDA ant.) in blinded, cont. trial of 31 pts.

–– No imp. No imp. with IV with IV lidocainelidocaine or morphineor morphine

•• May be variation of small fiber neuropathyMay be variation of small fiber neuropathy

FibromyalgiaTreatmentTreatment

FibromyalgiaTreatmentTreatment

Beneficial Beneficial Possibly BeneficialPossibly Beneficial

I i iI i iPregabalinPregabalin

DuloxetineDuloxetine

MilnacipranMilnacipran

ExerciseExercise

BCTBCT

ImipramineImipramine

FenfluramineFenfluramine

FluoxetineFluoxetine

NSAIDs (used NSAIDs (used alone)alone)BCTBCT

AmitriptylineAmitriptyline

ClomipramineClomipramine

alone)alone)

ZolpidemZolpidem

CyclobenzaprineCyclobenzaprine

AlprazolamAlprazolam

38

FibromyalgiaTentative Conclusions

FibromyalgiaTentative Conclusions

1 FM is clearly NOT a primary muscle dx1 FM is clearly NOT a primary muscle dx1. FM is clearly NOT a primary muscle dx.1. FM is clearly NOT a primary muscle dx.

2. FM is a “real” syndrome, as valid as any 2. FM is a “real” syndrome, as valid as any other in which criteria are clinical only.other in which criteria are clinical only.

3. FM is valuable concept for patient care3. FM is valuable concept for patient care

–– Avoids unnecessary testingAvoids unnecessary testing

–– Provides frame of reference for Provides frame of reference for patientpatient

–– Helps design therapeutic program Helps design therapeutic program

4. Diagnosis 4. Diagnosis notnot diagnosis of exclusion diagnosis of exclusion



Tender Tender

Normal

<5x nl

CK elevated

FET

Weak, abn EMG, CK


FM

Tender points

present?

PMR, MADStatins

Tender points

absent?

Repeat

<5x nl No other

abn

Biopsy

>5x normal,other sx

FET, Genetictesting

Biopsy

39

Muscle PainSummary

Muscle PainSummary

•• Consider carefully the type of painConsider carefully the type of pain

•• Concentrate exam on strength testing!Concentrate exam on strength testing!

–– Presence of tendernessPresence of tenderness

•• Evaluate further with CK, EMG, ESREvaluate further with CK, EMG, ESR

•• Do NOT automatically biopsy Do NOT automatically biopsy

Unrewarding most of the time!Unrewarding most of the time!–– Unrewarding most of the time!Unrewarding most of the time!

–– Only in selected casesOnly in selected cases

•• Consider statin myopathy, MADD, PMR, Consider statin myopathy, MADD, PMR, FM in patients with “normal everything”. FM in patients with “normal everything”.

Forearm Exercise TestMethodMethod

Forearm Exercise TestMethodMethod

•• IV in dominantIV in dominant antecubitalantecubital vein (23vein (23 gaga))IV in dominant IV in dominant antecubitalantecubital vein (23 vein (23 gaga))

–– Kept open with heparin/saline bolusesKept open with heparin/saline boluses

•• Draw baseline lactate and NHDraw baseline lactate and NH3 3 (on ice!)(on ice!)

•• Do not do Do not do ischemmicallyischemmically

•• Squeeze ball MAXIMALLY for 1 minuteSqueeze ball MAXIMALLY for 1 minute

–– Cuff deflatedCuff deflated

•• Lactate, NHLactate, NH3 3 at 1, 2, 4, 6, & 10 minat 1, 2, 4, 6, & 10 min

•• Do NOT do Do NOT do ischemicallyischemically (contracture(contracture)!)!

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